Lung cancer is the leading cause of cancer death in both men and women in the United States. The high mortality in patients with lung cancer results, in part, from the lack of effective tools to diagnose the disease at an early stage before it has spread to regional nodes or has metastasized beyond the lung. Our long-term goal is to develop a relatively noninvasive means of assessing the degree of airway epithelial cell damage and the risk for having or developing lung cancer among smokers. The objective of this application is to develop an intrathoracic (mainstem bronchus) airway gene expression profile capable of serving as an early diagnostic biomarker for lung cancer in smokers with clinical suspicion of disease. This approach is based on the hypothesis that patterns of gene expression in the histologically normal airway epithelium of a smoker reflect the types and degree of damage induced by the tobacco smoke and can predict that smoker's risk for having lung cancer. Using oligonucleotide microarrays, we have identified a gene expression signature in histologically normal large airway epithelial cells obtained at bronchoscopy that can serve as a highly sensitive and specific biomarker for distinguishing smokers with and without lung cancer. In this proposal, we will 1) validate this diagnostic airway biomarker in a large independent cohort of smokers with suspicion for lung cancer;2) evaluate our biomarker's accuracy in predicting the presence of lung cancer in stage 1 disease;3) integrate airway gene expression profiles with established clinical risk factors for disease to produce a clinicogenomic predictive model that can guide patient evaluation and management;4) develop a second gene expression signature in normal airway epithelium capable of distinguishing small cell vs. non-small cell lung cancer using novel reverse engineering algorithms. These studies will produce a relatively noninvasive tool effective in diagnosing lung cancer at an early and potentially curable stage. These gene expression-based biomarkers may eliminate the need for additional and often more invasive diagnostic tests that are costly, incur risk, and prolong the diagnostic evaluation of smokers with suspicion of lung cancer.